The present invention relates to a preparation for hormonal contraception. More specifically, the present invention relates to an ovulation-inhibiting preparation for hormonal contraception.
Hormonal ovulation inhibitors, which are orally administered in daily units, include combination preparations and sequential preparations. In combination preparations, a combination of an estrogen preparation and a gestagen preparation is administered for 21 days in constant or alternating, or absolute and/or relative dosing, to the extent that the desired cycle duration is 28 days. The estrogen preparation can be a natural estrogen or a synthetic ethinyl estradiol. After the administration of the aforementioned 21 daily units, this dosing is followed by a 7-day pause, whereby withdrawal bleeding simulating the natural menses occurs.
With typical sequential preparations that are given during a desired cycle duration of 28 days, a pure estrogen preparation is administered for 7 days and then a combination of an estrogen preparation and a gestagen preparation is administered for 15 days. An administration-free time of, for example, six days follows, during which withdrawal bleeding occurs. Although it is known to bridge the administration pause time in the combination and the sequential preparations with placebos for the sake of greater reliability of administration, no hormones of the type previously discussed have been administered during the approximately one-week administration pause to guarantee reliable withdrawal bleeding.
Only in substitution preparations have hormones been administered over the entire cycle. For example, a preparation has been administered in the following sequence: 10 days of an estrogen preparation, 11 days of a combination of estrogen and gestagen preparation, and 7 days of estrogen preparation in an especially low dose. These substitution preparations, however, are not suitable for inhibiting ovulation.
The sequential preparations used in substitution therapy are unsuitable for contraception, particularly because the natural estradiol does not prevent ovulation in the given dose and the phase during which gestagen is administered (i.e., 11 days) is too short. The sequential arrangement set forth above, however, does guarantee relatively good cycle control in the case of the substitution of preparations.
In general, the three most important aspects that are considered in hormonal contraception are contraceptive reliability, cycle control as well as minimum side-effects. The contraceptive reliability is based mainly on the action of the gestagen constituent. In a given preparation, gestagen is utilized in a dose that is approximately twice as high as the dose necessary for inhibiting ovulation. Added thereto are the peripheral effects of the gestagen on the cervix, fallopian tubes, and endometrium. Consequently, gestagen is present in an adequate dose in modern oral contraceptives in order to guarantee reliable contraception. The synthetic estrogen normally used, ethinyl estradiol, additionally intensifies the ovulation-inhibiting effect of the gestagen. Combined ethinyl estradiol-gestagen preparations that are taken over three of four weeks with an administration pause of 7 days have, hitherto, shown the greatest contraceptive reliability.
In contrast, the sequential preparations are somewhat less reliable in view of their contraceptive reliability, since 50 .mu.g ethinyl estradiol are administered during the pure estrogen phase which lasts about 7 days. This preparation does not prevent ovulation in all women, and also lacks the peripheral contraceptive effects of the gestagen. The ovulation-inhibiting dose (100% of women) of ethinyl estradiol is 100 .mu.g daily.
While the combination preparations described hereinabove offer the greatest contraceptive reliability among known ovulation inhibitors, the best cycle control (i.e., regular withdrawal menses with optimally few intermenses) is achieved with the use of sequential preparations, including those of the type that effect proliferation of the endometrium. This is due to the 7-day action of the estrogen (unimpeded by gestagen) prior to the gestagen being added. Beginning with the eighth day, further proliferation is inhibited and the endometrium is thereby altered. As previously noted, a menstruation-like withdrawal bleeding occurs approximately 2 to 3 days after the last estrogen-gestagen tablet is administered. In contrast, the proliferation of the endometrium is reduced from the very outset with the use of combination preparations, so that the cycle control in the latter case is poorer than with use of the sequential preparations.
With the use of ethinyl estradiol as the estrogen constituent in sequential preparations, it has been shown that higher doses are necessary, particularly during the initial phase in order to guarantee contraceptive effectiveness. However, this, in turn, creates a risk of serious and dangerous complications or side-effects (i.e., thromboembolism). The gestagen thus employed can intensify this effect in some cases. Further, this risk increases with increasing age, and is especially pronounced in women over 40 years of age.
One solution to the aforementioned problem would be the use of combination preparations which contain the natural estrogen, estradiol, instead of ethinyl estradiol. Based on substitution therapies involving post-menopausal women, it is known that treatment with estradiol involves substantially fewer health risks. However, estradiol is hardly suitable for use in combination preparations. Although the gestagen constituent in the combination preparation thereby guarantees reliable contraception, gestagen causes an intensified inactivation of the estradiol in the endometrium. This is due to the stimulation of local enzymes. The result is that the estrogen effect on the endometrium is greatly reduced, and intermenses frequently occur involving the disadvantageous effects set forth hereinabove. By contrast, ethinyl estradiol is metabolized far more slowly in the endometrium and, consequently, has an adequate effect on the endometrium.
U.S. Patent No. 4,921,843 discloses an ovulation-inhibiting preparation of the type, wherein an administration pause of at least one day is bridged with a placebo. The placebo is provided between the administration of the last daily hormone units (i.e., dragees, tablets, or the like) of the second hormone constituent and before the new daily hormone unit (i.e., the first of the first hormone constituent of the following cycle) is administered. This is in agreement with the previously prevailing opinion in this field, namely, an administration pause of at least one day. In the alternative, a drastic reduction in the effective estrogen level was considered absolutely necessary in order to trigger withdrawal bleeding. Even when a one-day administration pause is involved, however, such a discontinuation of the estrogen leads to modifications in the body's circulation, which can cause headaches (migraine attacks) and also lead to brief-durational changes in various metabolic parameters. In particular, hemostasis can be affected, so that a stable metabolism is out of equilibrium for one or more days because of the estrogen influence.
In the preparation for treating climacteric failure phenomena disclosed by German Published Application 26 45 307, an administration pause or, at least the simulation thereof with the temporary use of an especially weak type of estrogen that does not effect any adequate disturbance of the follicle stimulation, is considered necessary. Overall, the hormone doses used, in particular the duration of the gestagen phase, are therefore inadequate for contraception in view of the preparation disclosed in the aforementioned publication.
Similarly, German Published Application 24 31 704 discloses a preparation for alleviating climacteric complaints, wherein fluctuating estrogen concentrations are provided. The gestagen doses therefore only begin after the middle of the cycle, for which reason a contraceptive effect cannot be achieved. Moreover, a hormone-free pause in administration is absolutely prescribed.
European Published Application 0 368 373 discloses an ovulation-inhibiting preparation, whereby a constant gestagen level is provided over the entire cycle duration, and estrogen phases are cyclically superimposed thereon. One disadvantage of this preparation is an increased risk of intermanses. And although the constant gestagen administration, in fact, results in a good contraceptive effect, prolonged blood vessel-constriction occurs, so that adverse health effects are likely to occur, especially in women of increasing age and those having a tendency toward circulatory problems.